去泛素化酶BRCC3调控移植后aGVHD和GVL效应的分子机制研究

调控急性移植物抗宿主病（aGVHD）和移植物抗白血病（GVL）效应是移植领域的热点和难点。泛素-蛋白酶体途径可调控多个信号通路影响免疫细胞功能，项目组发现过表达去泛素化酶BRCC3能提高aGVHD小鼠生存，抑制T细胞激活和功能并减少靶器官中巨噬细胞的比例，通过泛素组学测序和质谱分析发现，BRCC3可能直接结合TRIM25从而调控T细胞和巨噬细胞。在aGVHD/GVL小鼠模型中，发现过表达BRCC3在抑制aGVHD的同时也能保留GVL效应，BRCC3可能是通过稳定TRIM25促进I型干扰素分泌进而增强GVL效应。基于上述研究，我们推测BRCC3是有效调控aGVHD和GVL效应的靶点。本项目将在敲基因小鼠模型中深入研究BRCC3调控aGVHD和GVL的分子机制，并探索BRCC3与临床aGVHD患者预后及复发的相关性，本研究将为靶向BRCC3调控移植后aGVHD和GVL提供重要的理论和实验基础。

The regulation of acute graft-versus-host disease (aGVHD) and graft-versus-leukemia (GVL) effects is the hot and difficult topic for allogeneic hematopoietic stem cell transplantation (allo-HSCT). The ubiquitin-proteasome pathway can regulate multiple signaling pathways to affect the function of immune cells. We previously found that overexpression of deubiquitinase BRCC3 could improve the survival of aGVHD mice, inhibit the activation and function of T lymphocytes and reduce the frequency of macrophages in target organs. We further found that BRCC3 might directly bind to the substrate protein TRIM25 to regulate T cells and macrophages. In the aGVHD/GVL mouse model, it was found that overexpression of BRCC3 could suppress the development of aGVHD and preserve GVL effects. BRCC3 might promote the secretion of type I interferons by stabilizing TRIM25 to enhance GVL effects. Based on the above findings, we speculated that BRCC3 could be a target to regulate aGVHD and GVL effects. In this study, we will further clarify the molecular mechanism of BRCC3 regulating aGVHD and GVL effects in BRCC3-KO mice models, and explore the correlations between BRCC3 and the prognosis and recurrence of patients with aGVHD. Collectively, our study will provide an important theoretical and experimental basis for targeting BRCC3 to regulate the effects of aGVHD and GVL after allo-HSCT.